Protecting groups for thiols

As Protecting Groups for Thiols for Suzuki-Miyaura Cross-Coupling.Ill... 

Scheme 11 Thiol ester as a protecting group for thiol...

Primary tritium isotope effect 849 Propellanes, synthesis of 569, 570 Protecting groups for thiols 432 acetamidomethyl 675, 676 acetyl and benzoyl 677, 678 benzyl 671, 672 benzyloxycarbonyl 678 benzylthiomethyl and phenylthio-methyl 681... 

Since the classic investigations of du Vigneaud and colleagues [1], thioethers have ranked as the best known and most widely used protective groups for thiols. Thioether derivatives of cysteine or other thiols are generally prepared by nucleophilic substitution reactions in which the sulphur functions as the nucleophile. These reactions frequently require either basic catalysis for the conversion of the thiol to the more highly nucleophilic mercaptide ion (eq. 7.1) or an acid catalyst (or... 

Acetamidoethyl)-4,S,6-trimethoxy-acetophenone, 56, 7 Acetamidoitiethyl group, for thiol protection, 59,194... 

DF Veber, JD Milkouski, SL Varga, RG Denkewalter, R Hirschmann. Acetamidomethyl. A novel thiol protecting group for cysteine. J Am Chem Soc 94, 5456, 1972. 

An alternative approach is the cleavage of a UV-active protecting group from the resin, such as the widely used Fmoc Test. The quantitation of the 9-fluorenyl-methyloxycarbonyl (Fmoc) protecting group for amines is used in SPPS as an indirect method to determine the extent of a peptide coupling reaction. Similar approaches have also been recently reported for the quantitation of supported thiols [151, 154] and have also been the subject of an excellent review [148]. 

Scheme 55 Photolabile protecting groups for alcohols and thiols.

Dihydropyran is of value as a protecting group for alcohols and phenols, and to a lesser extent amines, carboxylic acids and thiols (B-67MI22403, B-81MI22404). The resulting tetrahydropyranyl ethers (736) are stable to base, but are readily cleaved under acidic conditions (Scheme 284). 

The alkenic bond in dihydrothiopyrans in one case is a thioenol system in the other it is effectively an isolated double bond. The thioenol readily adds alcohols or thiols (c/. dihydropyran) it has been suggested as a protecting group for alcohols, and is readily removable with Ag+ under neutral conditions (66JOC2333). If conjugated with a carbonyl function, thiols will add under basic conditions (equation 34) (81JA4597). 

Most carbamates used as protective groups for amines are either acid-labile or base-labile. Deprotection proceeds by the mechanisms outlined in Figure 10.8. During the deprotection of acid-labile carbamates, carbocations are formed, which can alkylate electron-rich structural elements in a given substrate (e.g. phenols, thiols, indoles,... 

Another cyclic imide that has been used as a protective group for primary amines is the dithiasuccinoyl group (Dts) [230,303,304]. This group is stable towards acids (e.g. during deprotection of Boc-protected amines), but can be cleaved with thiols under basic conditions (2-mercaptoethanol (0.2 mol/L), NEt3 (0.5 mol/L), DCM, 25 °C, 5 min [303]). 

Yamashiro et al. 1972), boron trifluoride etherate in acetic acid (Schnabel et al. 1971), trimethylsylil triflate (Schmidt et al. 1987), trimethylsilyl perchlorate (Vorbrueggen Krolikiewicz 1975), and, most frequently, trifluoroacetic acid (Farowicki Kocienski 1995 and references therein). Deprotection of the /-HOC group under neutral conditions was not described until recently, yet it is highly desirable. Now it has been found that the tert-butoxycarbonyl protecting group for amines, alcohols, or thiols is removed efficiently (90-99% yield) with use of 0.2 equivalent of cerium ammonium nitrate in acetonitrile at 80°C (Hwu et al. 1996) ... 

A new and efficient route to endo-hirsutene has been described which uses, as the key step, the oxetane (11) from the intramolecular photocycloaddition of (12) (Rawal et ai), and 3-deoxy-D-arabino-2-heptulopyranosonic acids can be synthesised photochemically from Barton esters such as (13) (Barton and Liu). Interest in the development of photochemically removable protecting groups continues, and the irradiation of the 4-hydroxyphenacyl-protected system (14) is reported to release ATP with a quantum yield of 0.37 (Givens and Park). Benzoylbenzoate esters of primary and secondary alcohols undergo cleavage in the presence of electron donor molecules and it is proposed that such esters could be effective photolabile protecting groups for alcohols and that thiols can be similarly protected (Jones et al.). 

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